MedKoo product information:

Rubitecan

rubitecan is a semisynthetic agent related to camptothecin with potent antitumor and antiviral properties. Rubitecan binds to and inhibits the enzyme topoisomerase I and induces protein-linked DNA single-strand breaks, thereby blocking DNA and RNA synthesis in dividing cells; this agent also prevents repair of reversible single-strand DNA breaks. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

According to BioSpace, EuroGen Pharmaceuticals Ltd. has withdrawn its Marketing Authorisation Application for Orathecin™ (rubitecan), following discussions with the EMEA. Orathecin is a topoisomerase I inhibitor under development for the treatment of pancreatic cancer in patients who have failed at least one prior chemotherapy regimen. According to a press release from the EMEA, the Committee for Medicinal Products for Human Use (CHMP) reviewed Phase III data submitted as part of the application and did not consider it to be sufficient to demonstrate a clinical benefit for patients receiving Orathecin. The Company could not address the issues raised at this stage and therefore withdrew the application. Orathecin has orphan drug status in both the US and the EU. An ongoing US Phase II trial is looking at a combination of Orathecin and gemcitabine as a first-line combination therapy for advanced pancreatic cancer patients who are chemotherapy naive. See: http://www.nelm.nhs.uk/en/NeLM-Area/News/486153/486361/486372/.

Current developer:    EuroGen Pharmaceuticals Ltd.

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106: Kim JS, Amorino GP, Pyo H, Cao Q, Choy H. Radiation enhancement by the combined use of topoisomerase I inhibitors, RFS-2000 or CPT-11, and topoisomerase II inhibitor etoposide in human lung cancer cells. Radiother Oncol. 2002 Jan;62(1):61-7. PubMed PMID: 11830313.

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110: Kozuch P, Grossbard ML, Barzdins A, Araneo M, Robin A, Frager D, Homel P, Marino J, DeGregorio P, Bruckner HW. Irinotecan combined with gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (G-FLIP) is an effective and noncrossresistant treatment for chemotherapy refractory metastatic pancreatic cancer. Oncologist. 2001;6(6):488-95. PubMed PMID: 11743211.

111: Chatterjee D, Schmitz I, Krueger A, Yeung K, Kirchhoff S, Krammer PH, Peter ME, Wyche JH, Pantazis P. Induction of apoptosis in 9-nitrocamptothecin-treated DU145 human prostate carcinoma cells correlates with de novo synthesis of CD95 and CD95 ligand and down-regulation of c-FLIP(short). Cancer Res. 2001 Oct 1;61(19):7148-54. PubMed PMID: 11585748.

112: Han Z, Wyche JH, Sands H, Pantazis P. 9-Nitrocamptothecin is an effective drug for the treatment of human lung tumors: comparison of in vitro and in vivo studies. Anticancer Res. 2001 May-Jun;21(3B):1823-7. PubMed PMID: 11497265.

113: Hung CL, Doniger J, Palini A, Snyder SW, Radonovich MF, Brady JN, Pantazis P, Sadaie MR. 9-Nitrocamptothecin inhibits HIV-1 replication in human peripheral blood lymphocytes: a potential alternative for HIV-infection/AIDS therapy. J Med Virol. 2001 Jul;64(3):238-44. PubMed PMID: 11424110.

114: Chatterjee D, Wyche JH, Pantazis P. Up-regulation of cyclin B1 and cdc2 expression during 9-nitrocamptothecin-induced regression of DU145 prostate tumor. Anticancer Res. 2000 Nov-Dec;20(6B):4477-82. PubMed PMID: 11205291.

115: Verschraegen CF, Gilbert BE, Huaringa AJ, Newman R, Harris N, Leyva FJ, Keus L, Campbell K, Nelson-Taylor T, Knight V. Feasibility, phase I, and pharmacological study of aerosolized liposomal 9-nitro-20(S)-camptothecin in patients with advanced malignancies in the lungs. Ann N Y Acad Sci. 2000;922:352-4. PubMed PMID: 11193921.

116: Verschraegen CF, Vincent M, Abbruzzese JL, Siegler D, Kavanagh JJ, Loyer E, Kudelka AP, Rubin E. Phase I study of 9-nitro-20(S)-camptothecin in combination with cisplatin for patients with advanced malignancies. Ann N Y Acad Sci. 2000;922:345-8. PubMed PMID: 11193919.

117: Kemp KR, Liehr JG, Giovanella B. Combined radiation and 9-nitrocamptothecin (rubitecan) in the treatment of locally advanced pancreatic cancer. Ann N Y Acad Sci. 2000;922:320-3. PubMed PMID: 11193912.

118: Bernacki RJ, Pera P, Gambacorta P, Brun Y, Greco WR. In vitro antitumor activity of 9-nitro-camptothecin as a single agent and in combination with other antitumor drugs. Ann N Y Acad Sci. 2000;922:293-7. PubMed PMID: 11193904.

119: Verschraegen CF, Jaeckle K, Giovanella B, Knight V, Gilbert BE. Alternative administration of camptothecin analogues. Ann N Y Acad Sci. 2000;922:237-46. Review. PubMed PMID: 11193899.

120: Liehr JG, Harris NJ, Mendoza J, Ahmed AE, Giovanella BC. Pharmacology of camptothecin esters. Ann N Y Acad Sci. 2000;922:216-23. Review. PubMed PMID: 11193897.

121: Chow DS, Gong L, Wolfe MD, Giovanella BC. Modified lactone/carboxylate salt equilibria in vivo by liposomal delivery of 9-nitro-camptothecin. Ann N Y Acad Sci. 2000;922:164-74. PubMed PMID: 11193891.

122: Knight V, Kleinerman ES, Waldrep JC, Giovanella BC, Gilbert BE, Koshkina NV. 9-Nitrocamptothecin liposome aerosol treatment of human cancer subcutaneous xenografts and pulmonary cancer metastases in mice. Ann N Y Acad Sci. 2000;922:151-63. PubMed PMID: 11193890.

123: Cao Z, Pantazis P, Mendoza J, Early J, Kozielski A, Harris N, Vardeman D, Liehr J, Stehlin JS, Giovanella B. Structure-activity relationship of alkyl camptothecin esters. Ann N Y Acad Sci. 2000;922:122-35. PubMed PMID: 11193888.

124: Chatterjee D, Wyche JH, Romero DP, Pantazis P. Telomerase activity, Myc and Bcl-2: possible indicators of effective therapy of prostate cancer with 9-nitrocamptothecin. Anticancer Res. 2000 Sep-Oct;20(5A):2885-9. PubMed PMID: 11062697.

125: Pantazis P, Chatterjee D, Han Z, Wyche J. Differentiation of human malignant melanoma cells that escape apoptosis after treatment with 9-nitrocamptothecin in vitro. Neoplasia. 1999 Aug;1(3):231-40. PubMed PMID: 10935478; PubMed Central PMCID: PMC1508080.

126: Koshkina NV, Kleinerman ES, Waidrep C, Jia SF, Worth LL, Gilbert BE, Knight V. 9-Nitrocamptothecin liposome aerosol treatment of melanoma and osteosarcoma lung metastases in mice. Clin Cancer Res. 2000 Jul;6(7):2876-80. PubMed PMID: 10914737.

127: Knight V, Koshkina N, Waldrep C, Giovanella BC, Kleinerman E, Gilbert B. Anti-cancer activity of 9-nitrocamptothecin liposome aerosol in mice. Trans Am Clin Climatol Assoc. 2000;111:135-45. PubMed PMID: 10881338; PubMed Central PMCID: PMC2194367.

128: Wiernik PH. Current status of and future prospects for the medical management of adenocarcinoma of the exocrine pancreas. J Clin Gastroenterol. 2000 Jun;30(4):357-63. Review. PubMed PMID: 10875462.

129: Karaberis E, Mourelatos D. Enhanced cytogenetic and antitumor effects by 9-nitrocamptothecin and antineoplastics. Teratog Carcinog Mutagen. 2000;20(3):141-6. PubMed PMID: 10820424.

130: Amorino GP, Hercules SK, Mohr PJ, Pyo H, Choy H. Preclinical evaluation of the orally active camptothecin analog, RFS-2000 (9-nitro-20(S)-camptothecin) as a radiation enhancer. Int J Radiat Oncol Biol Phys. 2000 May 1;47(2):503-9. PubMed PMID: 10802379.

131: Rothenberg ML, Blanke CD. Topoisomerase I inhibitors in the treatment of colorectal cancer. Semin Oncol. 1999 Dec;26(6):632-9. Review. PubMed PMID: 10606256.

132: Koshkina NV, Gilbert BE, Waldrep JC, Seryshev A, Knight V. Distribution of camptothecin after delivery as a liposome aerosol or following intramuscular injection in mice. Cancer Chemother Pharmacol. 1999;44(3):187-92. PubMed PMID: 10453719.

133: Knight V, Koshkina NV, Waldrep JC, Giovanella BC, Gilbert BE. Anticancer effect of 9-nitrocamptothecin liposome aerosol on human cancer xenografts in nude mice. Cancer Chemother Pharmacol. 1999;44(3):177-86. PubMed PMID: 10453718.

134: Verschraegen CF, Gupta E, Loyer E, Kavanagh JJ, Kudelka AP, Freedman RS, Edwards CL, Harris N, Steger M, Steltz V, Giovanella BC, Stehlin JS. A phase II clinical and pharmacological study of oral 9-nitrocamptothecin in patients with refractory epithelial ovarian, tubal or peritoneal cancer. Anticancer Drugs. 1999 Apr;10(4):375-83. PubMed PMID: 10378672.

135: Pantazis P, Chatterjee D, Han Z, Wyche J. Modulation of 9-nitrocamptothecin-induced apoptosis by hyperthermia in human leukemia HL-60 cells. Anticancer Drugs. 1999 Mar;10(3):317-22. PubMed PMID: 10327039.

136: Han Z, Cao Z, Chatterjee D, Wyche J, Pantazis P. Propionate and butyrate esters of camptothecin and 9-nitrocamptothecin as antileukemia prodrugs in vitro. Eur J Haematol. 1999 Apr;62(4):246-55. PubMed PMID: 10227458.

137: Stehlin JS, Giovanella BC, Natelson EA, De Ipolyi PD, Coil D, Davis B, Wolk D, Wallace P, Trojacek A. A study of 9-nitrocamptothecin (RFS-2000) in patients with advanced pancreatic cancer. Int J Oncol. 1999 May;14(5):821-31. PubMed PMID: 10200331.

138: Sadaie MR, Doniger J, Hung CL, Pantazis P. 9-nitrocamptothecin selectively inhibits human immunodeficiency virus type 1 replication in freshly infected parental but not 9-nitrocamptothecin-resistant U937 monocytoid cells. AIDS Res Hum Retroviruses. 1999 Feb 10;15(3):239-45. PubMed PMID: 10052754.

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140: Singh S, Raju U, Mendoza J, Pantazis P, Aggarwal BB. Acquisition of cellular resistance to 9-nitro-camptothecin correlates with suppression of transcription factor NF-kappa B activation and potentiation of cytotoxicity by tumor necrosis factor in human histiocytic lymphoma U-937 cells. Anticancer Drugs. 1998 Sep;9(8):703-14. PubMed PMID: 9823429.

141: Arbuck SG, Takimoto CH. An overview of topoisomerase I-targeting agents. Semin Hematol. 1998 Jul;35(3 Suppl 4):3-12. Review. PubMed PMID: 9779876.

142: Herben VM, Ten Bokkel Huinink WW, Schellens JH, Beijnen JH. Clinical pharmacokinetics of camptothecin topoisomerase I inhibitors. Pharm World Sci. 1998 Aug;20(4):161-72. Review. PubMed PMID: 9762728.

143: Takimoto CH, Wright J, Arbuck SG. Clinical applications of the camptothecins. Biochim Biophys Acta. 1998 Oct 1;1400(1-3):107-19. Review. PubMed PMID: 9748525.

144: Pantazis P, DeJesus A, Early J, Giovanella B. Altered sensitivities to anticancer and differentiation agents in etoposide-resistant human myeloid leukemia U-937 cells. J Hematother. 1998 Feb;7(1):81-92. PubMed PMID: 9507384.

145: Verschraegen CF, Natelson EA, Giovanella BC, Kavanagh JJ, Kudelka AP, Freedman RS, Edwards CL, Ende K, Stehlin JS. A phase I clinical and pharmacological study of oral 9-nitrocamptothecin, a novel water-insoluble topoisomerase I inhibitor. Anticancer Drugs. 1998 Jan;9(1):36-44. PubMed PMID: 9491790.

146: Moulton S, Pantazis P, Epstein JS, Sadaie MR. 9-Nitrocamptothecin inhibits tumor recrosis factor-mediated activation of human immunodeficiency virus type 1 and enhances apoptosis in a latently infected T cell clone. AIDS Res Hum Retroviruses. 1998 Jan 1;14(1):39-49. PubMed PMID: 9453250.

147: Cao Z, Harris N, Kozielski A, Vardeman D, Stehlin JS, Giovanella B. Alkyl esters of camptothecin and 9-nitrocamptothecin: synthesis, in vitro pharmacokinetics, toxicity, and antitumor activity. J Med Chem. 1998 Jan 1;41(1):31-7. PubMed PMID: 9438019.

148: Saleem A, Ibrahim N, Patel M, Li XG, Gupta E, Mendoza J, Pantazis P, Rubin EH. Mechanisms of resistance in a human cell line exposed to sequential topoisomerase poisoning. Cancer Res. 1997 Nov 15;57(22):5100-6. PubMed PMID: 9371509.

149: Ahmed AE, Jacob S, Giovanella BC, Kozielski AJ, Liehr JG, Stehlin JS Jr. Comparative disposition of the antineoplastic agent 9-nitrocampotothecin and the inactive isomer 12-nitro camptothecin in CASE-bearing nude mice: effect of route of administration on tissue distribution. Cancer Chemother Pharmacol. 1997;41(1):29-36. PubMed PMID: 9443611.

150: Natelson EA, Giovanella BC, Verschraegen CF, Fehir KM, De Ipolyi PD, Harris N, Stehlin JS. Phase I clinical and pharmacological studies of 20-(S)-camptothecin and 20-(S)-9-nitrocamptothecin as anticancer agents. Ann N Y Acad Sci. 1996 Dec 13;803:224-30. PubMed PMID: 8993516.

151: Giovanella BC, Natelson E, Harris N, Vardeman D, Stehlin JS. Protocols for the treatment of human tumor xenografts with camptothecins. Ann N Y Acad Sci. 1996 Dec 13;803:181-7. Review. PubMed PMID: 8993511.

152: Liehr JG, Ahmed AE, Giovanella BC. Pharmacokinetics of camptothecins administered orally. Ann N Y Acad Sci. 1996 Dec 13;803:157-63. Review. PubMed PMID: 8993508.

153: Chatterjee D, Wyche JH, Pantazis P. Induction of apoptosis in malignant and camptothecin-resistant human cells. Ann N Y Acad Sci. 1996 Dec 13;803:143-56. PubMed PMID: 8993507.

154: Pantazis P, Chatterjee D, Wyche J, DeJesus A, Early J, Plaschke S, Giovanella B. Establishment of human prostate tumor xenografts in nude mice and response to 9-nitrocamptothecin in vivo and in vitro does not correlate with the expression of various apoptosis-regulating proteins. J Exp Ther Oncol. 1996 Sep;1(5):322-33. PubMed PMID: 9414421.

155: Pantazis P, Dejesus A, Early J, Rodriguez R, Chatterjee D, Han Z, Wyche J, Giovanella B. Development of human leukemia U-937 cell sublines resistant to doxorubicin: induction of differentiation and altered sensitivities to topoisomerase-directed drugs. Anticancer Res. 1995 Sep-Oct;15(5B):1873-81. PubMed PMID: 8572572.

156: Pantazis P, Harris N, Mendoza J, Giovanella B. The role of pH and serum albumin in the metabolic conversion of 9-nitrocamptothecin to 9-aminocamptothecin by human hematopoietic and other cells. Eur J Haematol. 1995 Sep;55(3):211-3. PubMed PMID: 7672097.

157: Khaoustov VI, Ozer A, Smith JR, Noda A, Mearns M, Krishnan B, Slagle BL, Yoffe B. Induction of senescent cell-derived inhibitor of DNA synthesis gene, SDI1, in hepatoblastoma (HepG2) cells arrested in the G2-phase of the cell cycle by 9-nitrocamptothecin. Lab Invest. 1995 Jul;73(1):118-27. PubMed PMID: 7603034.

158: Pantazis P, Vardeman D, Mendoza J, Early J, Kozielski A, DeJesus A, Giovanella B. Sensitivity of camptothecin-resistant human leukemia cells and tumors to anticancer drugs with diverse mechanisms of action. Leuk Res. 1995 Jan;19(1):43-55. PubMed PMID: 7837817.

159: Pantazis P, Harris N, Mendoza J, Giovanella B. Conversion of 9-nitro-camptothecin to 9-amino-camptothecin by human blood cells in vitro. Eur J Haematol. 1994 Oct;53(4):246-8. PubMed PMID: 7957812.

160: Pantazis P, Mendoza JT, DeJesus A, Rubin E, Kufe D, Giovanella BC. Partial characterization of human leukemia U-937 cell sublines resistant to 9-nitrocamptothecin. Eur J Haematol. 1994 Sep;53(3):135-44. PubMed PMID: 7925856.

161: Pantazis P, Mendoza J, DeJesus A, Early J, Shaw M, Giovanella BC. Development of resistance to 9-nitro-camptothecin by human leukemia U-937 cells in vitro correlates with altered sensitivities to several anticancer drugs. Anticancer Drugs. 1994 Aug;5(4):473-9. PubMed PMID: 7949254.

162: Hinz HR, Harris NJ, Natelson EA, Giovanella BC. Pharmacokinetics of the in vivo and in vitro conversion of 9-nitro-20(S)-camptothecin to 9-amino-20(S)-camptothecin in humans, dogs, and mice. Cancer Res. 1994 Jun 15;54(12):3096-100. PubMed PMID: 8205523.

163: Giovanella BC. New perspectives in colon cancer chemotherapy. Dis Colon Rectum. 1994 Feb;37(2 Suppl):S96-9. PubMed PMID: 8313802.

164: Pantazis P, Early JA, Mendoza JT, DeJesus AR, Giovanella BC. Cytotoxic efficacy of 9-nitrocamptothecin in the treatment of human malignant melanoma cells in vitro. Cancer Res. 1994 Feb 1;54(3):771-6. PubMed PMID: 8306340.

165: Pantazis P, Kozielski A, Rodriguez R, Petry E, Wani M, Wall M, Giovanella B. Therapeutic efficacy of camptothecin derivatives against human malignant melanoma xenografts. Melanoma Res. 1994 Feb;4(1):5-10. PubMed PMID: 8032218.

166: Rubin E, Pantazis P, Bharti A, Toppmeyer D, Giovanella B, Kufe D. Identification of a mutant human topoisomerase I with intact catalytic activity and resistance to 9-nitro-camptothecin. J Biol Chem. 1994 Jan 28;269(4):2433-9. PubMed PMID: 8300570.

167: Pantazis P, Early JA, Kozielski AJ, Mendoza JT, Hinz HR, Giovanella BC. Regression of human breast carcinoma tumors in immunodeficient mice treated with 9-nitrocamptothecin: differential response of nontumorigenic and tumorigenic human breast cells in vitro. Cancer Res. 1993 Apr 1;53(7):1577-82. PubMed PMID: 8453626.

168: Pantazis P, Kozielski AJ, Mendoza JT, Early JA, Hinz HR, Giovanella BC. Camptothecin derivatives induce regression of human ovarian carcinomas grown in nude mice and distinguish between non-tumorigenic and tumorigenic cells in vitro. Int J Cancer. 1993 Mar 12;53(5):863-71. PubMed PMID: 8449612.

169: Pantazis P, Mendoza JT, Early JA, Kozielski AJ, Natelson EA, Giovanella BC. 9-Nitro-camptothecin delays growth of U-937 leukemia tumors in nude mice and is cytotoxic or cytostatic for human myelomonocytic leukemia lines in vitro. Eur J Haematol. 1993 Feb;50(2):81-9. PubMed PMID: 8440362.

170: Pantazis P, Kozielski AJ, Vardeman DM, Petry ER, Giovanella BC. Efficacy of camptothecin congeners in the treatment of human breast carcinoma xenografts. Oncol Res. 1993;5(8):273-81. PubMed PMID: 8012059.